Field of Invention
This invention comprises compounds, pharmaceutical compositions and methods of use of the compounds and compositions containing them. This invention relates more particularly to certain sulfonamidoquinoline compounds and pharmaceutical compositions thereof, and to methods of inhibiting ubiquitination. Further methods comprise treating and/or preventing disease using certain sulfonamidoquinoline compounds to block the degradation of tumor suppressors.
Technical Background
Ubiquitination of a protein provides a signal for its targeted degradation and recycling via the ubiquitin-proteasome pathway. The process of ubiquitination takes place in a series of steps, beginning with the activation of ubiquitin through a ubiquitin-activating enzyme E1 and the transfer to a ubiquitin-conjugating enzyme E2. Finally the ubiquitin is linked to the lysine of the target protein in the presence of an ubiquitin-protein ligase E3 (referred to as a ubiquitin ligase). Chains of four or more ubiquitin domains activates the degradation process by the proteasome.
The E3 ubiquitin ligase acts as a substrate recognition module for the ubiquitination system in which each E3 provides specificity for only a small number of substrates. This specificity makes E3 ligases attractive targets for drug discovery (analogous to kinases), for instance by preventing degradation of pro-apoptotic proteins in cancer cells.
The development of small molecule E3 ligase inhibitors is challenging due to the requirement of the molecules to disrupt protein-protein interactions (PPI's). PPI's are an area that has not been well explored in small-molecule drug-discovery because the interaction surfaces are often large with flat or shallow grooves at the interfaces. This is in contrast to the tight, well defined pockets present in traditional enzymes or receptors. However, it has the potential to be rewarding and is beginning to be recognized, and there have been several examples of the disruption of E3 ligase binding. One of the initial investigations in this area came from work on the disruption of binding between p53 and MDM2. MDM2 serves as the E3 ligase for p53 promoting degradation. The work resulted in the identification of cis-imidazolines known as Nutlins, which displace p53 from its complex with MDM2 in the 100-300 nM range. These efforts have spurred an effort to develop structure-activity relationships (SAR) around these and similar structures, resulting in compounds that inhibit the p53-MDM2 interaction with single digit nanomolar potencies and below. Further, there have been several reports of small molecules being used to target E3 ligases including the von Hippel-Lindau ligase to disrupt the VHL-HIF-1α interaction as well as a non-ligase PPI between HIF1α and HIF1α.
The Skp1-Cullin 1-F-Box (SCF) family of E3 ligases are a well characterized family held together through PPI's. The complex consists of the scaffold protein Cullin-1, which binds Roc1 (recruiting the E2) and Skp1 (recruiting the F-Box protein). One particular E3 ligase complex is responsible for p27, the substrate recognition component Skp2 and an adaptor protein Cks1. p27, a CDK inhibitor, is a negative regulator of cell cycle progression. Low levels of p27 have been implicated in a number of cancers, while elevated levels of Cks1 have been associated with low levels of p27 and poor prognosis in cancer patients. There have been several groups that have targeted the SCF ligases with the goal of increasing levels of p27. Molecules have also been identified as disrupting PPI's between Skp1-Skp2 and Skp2-Cks1-p27, and as interacting with alternative E3 ligases in the SCF system including Cdc4, Met30 and βTRCP1. There have not been any reports of compounds targeted to the Cks1-Skp2 PPI.